Ono Kento, Horiguchi Hiroto, Iyama Satoshi, Sato Ken, Ibuki-Shimoyama Saori, Shirato Shotaro, Sugama Yusuke, Goto Akari, Kobune Masayoshi
Department of Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-Ku, Sapporo, 060-8543, Japan.
Int J Hematol. 2025 Apr 27. doi: 10.1007/s12185-025-03985-3.
Neuropeptides are chemical messengers that are synthesized and released by nerve cells. Studies suggest that neuropeptides released from the nervous system in bone marrow may be involved in the regulation of hematopoiesis and survival of leukemic stem cells (LSC). Parathyroid hormone 2 receptor (PTH2R), a new LSC marker, is expressed on CD34 + leukemic cells. Its ligand, tuberoinfundibular peptide of 39 residues (TIP39), is expressed in the nervous system. However, the role of the TIP39-PTH2R axis in leukemic cells is unclear. We investigated the function of this axis in leukemic cell lines, as well as primary CD34 + myelodysplastic syndrome (MDS) and AML cells. Expression of PTH2R mRNA was higher in primary CD34 + MDS (GSE58831) or CD34 + CD38-AML (GSE24395) cells than in healthy volunteers. TIP39 reduced apoptosis in the leukemic cell lines Kasumi-1 and SKM-1. LC3-II expression was increased after incubation with TIP39, and was augmented in leukemic cell lines treated with lysosome inhibitors. This suggests that TIP39 could induce autophagy. Analysis of a public database (GSE58831) showed that high PTH2R expression was associated with poor overall survival and was an independent prognostic factor in MDS/AML patients. Our results suggest that the TIP39-PTH2R axis is a potential therapeutic target.
神经肽是由神经细胞合成和释放的化学信使。研究表明，骨髓中从神经系统释放的神经肽可能参与造血调节和白血病干细胞（LSC）的存活。甲状旁腺激素2受体（PTH2R）是一种新的LSC标志物，在CD34 +白血病细胞上表达。其配体，39个残基的结节漏斗肽（TIP39），在神经系统中表达。然而，TIP39-PTH2R轴在白血病细胞中的作用尚不清楚。我们研究了该轴在白血病细胞系以及原发性CD34 +骨髓增生异常综合征（MDS）和AML细胞中的功能。原发性CD34 + MDS（GSE58831）或CD34 + CD38-AML（GSE24395）细胞中PTH2R mRNA的表达高于健康志愿者。TIP39减少了白血病细胞系Kasumi-1和SKM-1中的细胞凋亡。与TIP39孵育后，LC3-II表达增加，并且在用溶酶体抑制剂处理的白血病细胞系中增强。这表明TIP39可以诱导自噬。对公共数据库（GSE58831）的分析表明，高PTH2R表达与总体生存率低相关，并且是MDS/AML患者的独立预后因素。我们的结果表明，TIP39-PTH2R轴是一个潜在的治疗靶点。
